Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Li].Cl[S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([O:31]C)=[O:30])=[N:27][CH:28]=1)(=[O:22])=[O:21].[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=1)(=[O:21])=[O:22]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cn1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)nc2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 961 mg, 3.84 mmol, 1.0 eq) was suspended in THF (10 ml) and stirred at −78° C. for 10 minutes. 1,1,1,3,3,3-Hexanemethyldisilazane lithium salt (LiHMDS, 1M in THF, 4.2 ml, 4.2 mmol, 1.1 eq) was added dropwise maintaining the temperature below −70° C. and the reaction mixture stirred for a further 30 minutes. A solution of methyl 5-(chlorosulfonyl)pyridine-2-carboxylate (Preparation 16, 1 g, 3.8 mmol, 1 eq) in THF (5 ml) was added dropwise maintaining the reaction temperature below −72° C. and the reaction mixture allowed to warm to room temperature for 2 hours. The reaction mixture was diluted with water (10 ml), extracted into ethyl acetate (5 ml), dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was dissolved in dioxane (5 ml), a solution of sodium hydroxide (311 mg, 7.77 mmol, 2 eq) in water (2 ml) was added and the reaction mixture stirred at room temperature for 30 minutes. The MeOH was evaporated and the remaining aqueous solution washed with ethyl acetate (10 ml). Brine (10 ml) was added to the aqueous phase and the solution extracted with ethyl acetate (10 ml). A precipitate formed in the organic phase which was collected by filtration to yield the title compound as a white solid (415 mg, 0.95 mmol, 25%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[C:22]([O:26][C:27](=[O:54])[N:28]([C@@H:42]([C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1)[CH3:43])[CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH:31]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1.O>[C:5]([C:4]1[CH:7]=[C:8]([F:11])[C:9]([N:33]2[CH2:34][CH2:35][CH:30]([CH2:29][N:28]([C@@H:42]([C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH:47]=[CH:46][CH:45]=3)[CH3:43])[C:27](=[O:54])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:31]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:32]2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2c(F)cc(C#N)cc2F)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To a mixture of 96 mg of 3,4,5-trifluorobenzonitrile, 113 mg of potassium carbonate, and 3.0 mL of DMSO was added a solution of 181 mg of a crude product of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate in 3.0 mL of THF, the reaction vessel was tightly sealed, and the mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 232 mg of tert-butyl {[1-(4-cyano-2,6-difluorophenyl)-3-phenylpiperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a crude product. FAB+: 582
Reaction SMILES: Cl[C:2]1[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:12][C:3]=1[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C.O>O1CCCC1>[O:25]1[CH2:26][CH2:27][N:22]([C:2]2[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:12][C:3]=2[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5])[CH2:23][CH2:24]1
Reactant: O=C(OCC(F)(F)F)c1ccc(OCC(F)(F)F)nc1Cl
Reactant: C1COCCN1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCC(F)(F)F)c1ccc(OCC(F)(F)F)nc1N1CCOCC1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 101.3 %

Procedure:
A mixture of 2,2,2-trifluoroethyl 2-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (0.30 g, 0.89 mmol, Step-1), morpholine (0.77 mL, 8.89 mmol) and triethylamine (0.62 mL, 4.44 mmol) in tetrahydrofuran (2 mL) is stirred at 140° C. for 10 minutes under microwave irradiation. The reaction mixture is poured into water and extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo to give 0.35 g (>99% yield) of the title compound as a yellow solid. This material is used for the next reaction (Step-3) without further purification.
Reaction SMILES: C(OC([CH:8]1[NH:13][CH2:12][C:11]2[S:14][C:15]([C:17]([NH:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[C:25]([O:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH:24]=3)[OH:22])=[O:18])=[N:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[N:16]1[C:10]2[CH2:9][CH2:8][NH:13][CH2:12][C:11]=2[S:14][C:15]=1[C:17]([NH:19][CH2:20][CH:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([O:38][CH2:39][C:40]([OH:42])=[O:41])[CH:24]=1)[OH:22])=[O:18]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(O)CNC(=O)c2nc3c(s2)CNC(C(=O)OC(C)(C)C)C3)cc1OCC(=O)OC(C)(C)C
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(C(O)CNC(=O)c2nc3c(s2)CNCC3)cc1OCC(=O)O
Yield: 77.8 %

Procedure:
To the solution of the compound prepared in (a) (115.3 mg, 0.174 mmole) in anisole (0.5 ml) was added trifluoroacetic acid (2.0 ml) at 0° C. Crystals were deposited by the addition of isopropyl ether at 0° C., collected by filtration, and lyophilized to give 82.1 mg of a crude product, which was purified on a LH column (50% methanol) to give 76.6 mg of the title compound as a colorless crystal (yield, 77.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[CH3:23]C(C)([O-])C.[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH3:23])[CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 0 °C

Procedure:
In one portion, 0.7 g (2.2 mmole) of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.3 g (2.6 mmole) of potassium t-butoxide in 30 ml of dry dimethylformamide which was cooled to 0° C. After stirring for 15 minutes 1.0 ml (16 mmole) of methyl iodide was added, and the mixture was allowed to warm to room temperature. Water was added, and the mixture was extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a yellow oil. Purification by column chromatography (silica gel, 20 g; eluent 5% ether in methylene chloride) gave a tan solid (mp 142°-144° C.). Recrystallization from a mixture of ether and petroleum ether gave cream colored prisms, mp 144°-146° C.
Reaction SMILES: C([N:8]([C@@H:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C@@H](C)C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:8][C@@H:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@@H](C)[C@H](c1ccccc1)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](C)[C@@H](N)c1ccccc1

Procedure:
A mixture of methyl (2S,3R,αS)-3-(N-benzyl-N-a-methylbenzylamino)-2-methyl-3-phenylpropionate (13.0 g, 33.55 mmol) and 10% palladium-on-carbon (13.0 g) in glacial acetic acid (260 ml) was hydrogenated under a balloon of hydrogen for 24 h. The catalyst was removed by filtration followed by evaporation and co-distillation with toluene to provide the title compound as a white solid. MS (m/z): 194.2 (M+H)+ ; C11H15NO2 requir. 193.3.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][N:16]=1)#[CH:14]>O1CCOCC1.O.CCOC(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([C:13]2[N:3]=[N:2][N:1]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:11][CH:12]=3)[CH:14]=2)=[N:16]1
Reactant: C#Cc1n[nH]c2ccccc12
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reaction time: 48 h
Yield: 106 %

Procedure:
4-azidobenzoic acid (252 mg; 1.55 mmol; 1.1 eq.) and 3-ethynyl-1H-indazole (200 mg; 1.4 mmol; 1.0 eq.) were dissolved in 1,4-dioxane (3 mL). D-(−)-isoascorbic acid sodium salt (28 mg; 0.14 mmol; 0.1 eq.) followed by a solution of copper sulfate pentahydrate (7 mg; 0.03 mmol; 0.02 eq.) in water (0.75 mL) were added and the reaction mixture was stirred at 900 for 48 h. Reaction mixture was diluted with EtOAc and extracted with a NaOH (0.1N). Aqueous phase was filtered, acidified to pH 4-5 by addition of HCl (5N) and the precipitate thus obtained, was filtered, washed with water and dried under reduced pressure at 50° C. to afford the title compound as a white solid (453 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 13.53 (s, 1H), 9.57 (s, 1H), 8.49 (d, J=8.1 Hz, 1H), 8.42-8.24 (m, 3H), 8.13-8.03 (m, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.63-7.50 (m, 1H), 7.45-7.29 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].[C:14]([O-])([O-])=O.[K+].[K+].CI.CN([CH:25]=[O:26])C>>[CH3:14][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:26][CH3:25])=[O:6]
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: [K+]
Solvent: CI
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 73.5 %

Procedure:
To a mixture of 3-hydroxy-4-nitrobenzoic acid (203 g, 1.109 mol) and K2CO3 (345 g, 2.496 mol) in DMF (3000 mL) was added drop wise CH3I (400 g, 2.817 mol) at ambient temperature. The mixture was stirred at ambient temperature for 13 h. TLC (EtOAc: Petroleum ether 1:4) indicated the reaction was complete. Most of the solvent was removed under reduced pressure and the residue was diluted with water (2 L). Then the mixture was extracted with EtOAc (2 L×3). The combined organic layers were washed with water (1L×3), dried over Na2SO4 and concentrated under reduced pressure to yield the desired ester (172 g, 73.5%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.848-7.827 (d, 2H), 7.759 (s, 1H), 7.705-7.681 (d, 1H), 4.018 (s, 3H), 3.969 (s, 3H).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH3:6])([O-:3])=[O:2].C=O.[C:9](=S)=S.[CH3:12][N:13]([CH3:17])[C:14](=[S:16])[S-:15].C[NH2+]C>CO.O>[CH3:12][N:13]([CH3:17])[C:14](=[S:15])[S:16][CH2:9][CH:4]([N+:1]([O-:3])=[O:2])[CH2:5][CH3:6]
Reactant: CCC[N+](=O)[O-]
Reactant: S=C=S
Reactant: CN(C)C(=S)[S-]
Agent: C=O
Agent: C[NH2+]C
Solvent: CO
Solvent: O
Product: CCC(CSC(=S)N(C)C)[N+](=O)[O-]
Reaction time: 21.5 h

Procedure:
Nitropropane (17.8 grams, 0.20 mole), formaldehyde (16.2 grams of 37% aqueous solution, 0.20 mole), carbon disulfide (15.2 grams, 0.20 mole), and dimethylammonium dimethyldithiocarbamate (33.2 grams, 0.20 mole) were dissolved in methanol (100 ml.). A mildly exothermic reaction resulted. After 21.5 hours, the reaction mixture was poured into water (850 ml.) and the precipitated oil was washed with water and then taken up in methylene chloride. The dried solution was concentrated in a rotary evaporator to leave an amber oil. A small sample of the product was chromatographed on Florisil adsorbant giving an oil which solidified when chilled in methanol solution. The main sample crystallized from cold methanol solution when it was seeded. Repeated recrystallization from cold methanol gave pure 2-nitrobutyl dimethyldithiocarbamate melting at about 23° C. The structure was determined from infrared and nuclear magnetic resonance spectra and elemental analysis.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([NH2:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:12]([NH:28][C:2]1[N:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cn1

Procedure:
A mixture of 5.13 g. of methyl 6-chloronicotinate, 7.23 g. of hexadecylamine and 150 ml. of hexamethylphosphoramide is stirred at 130° for 6 hours. Cooling and dilution with water affords a precipitate which is collected by filtration and recrystallized from ethyl acetate and then from acetone to yield methyl 6-hexadecylamino-3-pyridinecarboxylate as a tan solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:29][O:30]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:29]([C:18]1[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])=[O:30]
Reactant: COC(Cl)Cl
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
To a solution of N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (650 mg, 1.71 mmol) obtained in Example 3 and 1,1-dichloromethyl methyl ether (237 mg, 2.06 mmol) in dichloromethane (5 mL) was added dropwise at 0° C. under an argon atmosphere and ice-cooling titanium tetrachloride (0.34 mL, 3.07 mmol), and the mixture was stirred at the same temperature for 20 minutes. Water was added to the reaction solution and the product was extracted with dichloromethane. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 520 mg (yield: 75%) of the title compound. Melting point: 177-178° C (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[NH2:9][C:10]1[S:11][CH:12]=[N:13][N:14]=1>C(O)C>[ClH:1].[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:14]1[N:13]=[CH:12][S:11][C:10]1=[NH:9]
Reactant: ClCc1ccccn1
Reactant: Nc1nncs1
Solvent: CCO
Product: Cl
Product: N=c1scnn1Cc1ccccn1
Temperature: 25 °C
Yield: 27.6 %

Procedure:
A mixture of 2-chloromethylpyridine (1.75 g, 0.0137 M) and 2-amino-1,3,4-thiadiazole (1.09 g, 0.0108 M) in 20 mL ethyl alcohol was refluxed for 20 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was washed with ethyl acetate and dried to yield 0.680 g of the title compound. MP=187-189° C. 1H-NMR (DMSO-d6) δ 10.6 (br s, 1H), 9.0 (s, 1H), 8.5 (d, 1H), 7.9 (m, 1H), 7.48 (d, 1H), 7.38 (m, 1H), 5.7 (s, 2H). 13C-NMR (DMSO-d6) δ 167.7, 153.0, 149.3, 145.0, 137.4, 123.4, 122.4, 54.0. Mass spectrum: m/e=193 (p+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16]O)[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:19].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH2:38].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][NH:39][CH2:40][CH:41]2[CH2:42][CH2:43][CH2:44][O:38]2)[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:19]
Reactant: O
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CCO)cc1Cl
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CCNCC2CCCO2)cc1Cl
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Compound 102 (0.15 g, 0.41 mmol) was dissolved in pyridine (0.2 mL) at 0° C., and p-toluenesulfonyl chloride (0.086 g, 0.45 mmol) was added. The suspension was stirred for 45 min at 0° C., after which the amine (tetrahydro-furfuryl amine, 0.127 mL, 1.23 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. H2O (10 mL) was added and the aqueous phase was extracted with EtOAc (5×10 mL). The combined organic phases were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography using EtOAc/MeOH/Et3N 10:1:0.1 as the eluent to afford the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=O)=[CH:4][CH:3]=1.I.CS[C:15](=[NH:28])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=1>N1C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]2[NH:28][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:18][C:19]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NNC(=O)c1ccc(O)cc1
Agent: I
Solvent: c1ccncc1
Product: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)cc1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
4-hydroxybenzoic acid hydrazide (3.0 g, 19.66 mmol) and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (7.8 g, 19.66 mmol) were suspended in 100 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours under Ar atmosphere. Then it was cooled down to ambient temperature and pyridine was removed in vacuo. The resulting yellow oil was re-dissolved in a small amount of ethyl acetate, loaded on a short pad of silica gel and eluted with 5:1 hexane/ethyl acetate, then with 100% ethyl acetate to collect the product. The product was re-purified by a second silica gel column chromatography, using ISCO system (80 g pre-packed column, 25 min run, 20% to 50% EtOAc gradient in hexane). Solvent was removed in vacuo to give the title product as a white solid (2.83 g). Yield 40.4%.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[O:15][CH3:16].O.I([O-])(=O)(=O)=O.[Na+].[Cl-].[Na+]>CO.O1CCCC1>[CH3:16][O:15][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[CH2:3][CH:2]=[O:1])[NH:11][C:10](=[O:14])[CH2:9][CH2:8]2
Reactant: COc1cc2c(cc1CC(O)CO)NC(=O)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1CC=O)NC(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
110 mg of 7-(2,3-dihydroxypropyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one was dissolved in 2 ml of methanol and 1 ml of tetrahydrofuran. Thereafter, 2 ml of water containing 0.16 g of sodium metaperiodate was added to the reaction solution while cooling on ice. The obtained mixture was stirred at room temperature for 30 minutes. A saturated sodium chloride aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 87 mg of (6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)acetaldehyde. This compound was directly used in the following reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][CH2:13][CH2:14][NH:15][CH3:16]>>[NH2:1][C:2]1[C:3]([C:8]([N:15]([CH2:14][CH2:13][O:12][CH3:11])[CH3:16])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: CNCCOC
Product: COCCN(C)C(=O)c1ncccc1N
Yield: 85 %

Procedure:
According to the procedure described in example 29, 3-aminopicolinic acid was reacted with 2-methoxy-N-methylethanamine to give the title compound (85%) as colourless viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17](O)=[O:18])[CH:13]=3)[C:8]2=[O:20])=[CH:4][CH:3]=1.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][CH2:32][NH2:33]>>[Cl-:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([NH:33][CH2:32][CH2:31][CH2:30][NH+:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]4[CH3:23])=[O:18])[CH:13]=3)[C:8]2=[O:20])=[CH:21][CH:22]=1
Reactant: CC1CCCCN1CCCN
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1ccc(Cl)cc1)C2=O
Product: CC1CCCC[NH+]1CCCNC(=O)c1ccc2c(c1)C(=O)N(Cc1ccc(Cl)cc1)C2=O
Product: [Cl-]

Procedure:
2-(4-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 3-(2-methylpiperidin-1-yl)propan-1-amine (138 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 136 mg (87%) was obtained by following the procedure described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][OH:8].C(OC(OCC)[CH:18]([Cl:20])[CH3:19])C.[N+]([CH3:27])([O-])=O>B(F)(F)F>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:27]([CH2:19][CH2:18][Cl:20])[O:8][CH2:7][CH2:6]2
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(CCO)cc1OC
Reactant: CCOC(OCC)C(C)Cl
Agent: FB(F)F
Product: COc1cc2c(cc1OC)C(CCCl)OCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-dimethoxyphenethyl alcohol (110 g, 1.233 mole) and chloropropionaldehyde diethyl acetal (40 ml) in 240 ml of nitromethane, 8 ml of BF3 etherate is added. The mixture is stirred for 2 hours at room temperature under N2. This, after work up from water and extracting with methylene chloride gives a yellow oil. This, after column chromatography (silica gel), gives 45 g (oil) of 6,7-dimethoxy-1-(2-chloroethyl)isochroman which is crystallized from ether/pet. ether to give 41 g (70%) of 6,7-dimethoxy-1-(2-chloroethyl)isochroman as a white crystalline material, m.p. 56°-57.5°.